Catalyzing New Treatments

Many of the most transformative medicines used today to treat conditions such as high blood pressure, high cholesterol, and various forms of cancer can be traced back to fundamental research into the most basic processes inside our cells and their building blocks.

But harnessing such basic insights gleaned in the lab to create treatments that can transform human lives in the clinic and at the bedside has often been a sinuous and often dead-end journey.

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The recently established Blavatnik Therapeutics Challenge Awards (BTCAs) at Harvard Medical School are designed to propel precisely such scientific work—research with exceptional promise for therapeutic translation.

The awards are part of the School’s Therapeutics Initiative, an effort to enhance HMS’ traditional strength in fundamental discoveries of the basic mechanisms of biology and disease to advance new treatments to the clinic. The initiative and the awards were made possible by a transformational gift from the Blavatnik Family Foundation.

Now in their second year, the 2021 BTCA grants have been awarded to projects researching fatal telomere diseases, congenital deafness-and-blindness syndromes, blood disorders, and skeletal conditions. Each will receive $1 million over two years to advance the work.

“This year’s winning projects yet again show how advances in basic research can be thoughtfully translated towards an impactful medicine,” said Mark Namchuk, executive director of therapeutic translation at HMS. “Each one of them shows exceptional promise to propel fundamental knowledge into frontline therapy.”

The 2021 award-winning projects are:

Identifying small-molecule therapies for telomere diseases (principal investigator Suneet Agarwal, HMS associate professor of pediatrics at Boston Children’s Hospital)

• The challenge: Telomere diseases encompass a spectrum of rare and often-fatal syndromes, including dyskeratosis congenita (DC) and pulmonary fibrosis (PF), caused by mutations in genes regulating the biology and function of telomeres, the tiny caplike structures at the ends of chromosomes that shield them from fraying and damage. The cardinal feature of DC is bone marrow failure and deficient blood cell production. PF involves the progressive scarring and damage to lung cells and the ultimate failure of the lungs in patients affected by the disease. Despite genetic discoveries in the past two decades, there has been no translation of this new knowledge and there are no curative therapies for these conditions.
  
• A possible solution: Studying genetic mutations in patients with DC, Agarwal’s team has identified post-transcriptional factors that regulate accumulation of a substance known as noncoding telomerase RNA component (TERC). The research showed that inhibiting one of these factors restores TERC and telomere maintenance in induced pluripotent stem cells (iPSCs) from DC patients. Furthermore, the team has identified small molecules that restore telomeres in the cells derived from patients with DC. The goal of this project is to advance small-molecule treatments for clinical testing and, ultimately, lead to a new treatment approach for telomere diseases and other degenerative disorders that may be driven by a similar dysfunction in these structures.

Gene therapy for congenital deafness and blindness (principal investigator David Corey, Bertarelli Professor of Translational Medical Science, in the Blavatnik Institute at HMS)

• The challenge: Usher syndrome is a rare but devastating hereditary deafness-and-blindness condition, caused by mutation of any of nine genes. Mutations in one particular gene, PCDH15, can lead to Usher syndrome type 1F, a severe form of the disease that manifests with profound deafness and lack of balance at birth, and progressive blindness developing over several decades. There is no treatment.
  
• A possible solution: Corey’s laboratory will collaborate with the lab of Artur Indzhykulian at Mass Eye and Ear to develop a gene-therapy strategy for Usher syndrome type 1F and to facilitate its path to the clinic. The gene that needs to be delivered, however, is too large to “pack” as cargo in an adeno-associated virus capsule—the traditional gene-delivery vehicle. To overcome this hurdle, the team engineered smaller but still functional protein versions that fit in the viral capsule. These mini-PCDH15 genetic constructs have successfully rescued the hearing of a mouse model of Usher syndrome 1F. The researchers plan to use these constructs to rescue the vestibular function of mice with Usher 1F mutations, to rescue the vision in zebrafish with the same mutation and to test localization and toxicity in the eyes and ears of nonhuman primates.

Protein therapy for frozen shoulder (principal investigator Ara Nazarian, HMS professor of orthopedic surgery at Beth Israel Deaconess Medical Center)

• The challenge: Frozen shoulder is a common degenerative inflammatory condition affecting the shoulder joint and leads to pain, stiffness, and loss of function. Nonsurgical treatment options provide marginal improvement and do not address the underlying disease pathology—the progressive and irreversible accumulation of scar tissue in and around the joint. Physical therapy is the main treatment, with surgical interventions used in severe cases. However, surgery can lead to complications, and the condition has high recurrence rates.
  
• A possible solution: Nazarian’s team has developed a first-of-its-kind approach using a synthetic version of a human protein known for its antifibrotic effects on joints and other structures, and also plays a key role during pregnancy. The researchers plan to deliver into the joint and to the site of fibrosis a protein called human relaxin-2, wrapped in a polymeric microcapsule for prolonged and local release. The idea originated with observations made by Beth Israel Deaconess orthopedic surgeon Edward Rodriguez in a group of female patients with arthrofibrosis who experienced lasting motion restoration and reduced joint pain during and after pregnancy when the levels of relaxin hormone naturally rise. If successful, the treatment could transform the management of shoulder arthrofibrosis and other similarly affected joints.

Treating pediatric anemia with gene therapy (principal investigator Vijay Sankaran, HMS associate professor of pediatrics at Boston Children’s Hospital)

• The challenge: Diamond-Blackfan anemia (DBA) is a genetic condition that affects the function of bone marrow, the body’s factory for blood cells. In DBA, the bone marrow fails to produce enough red blood cells, leading to a range of complications including a higher risk for developing certain cancers. The bone marrow malfunction arises from defects in one of more than two dozen genes that lead to impaired mRNA translation of a key protein, called GATA1, which regulates the synthesis of red blood cells. Current treatments for DBA are sub-optimal and are associated with considerable morbidity and health care expenditures.
  
• A possible solution: The research team led by Sankaran will design a novel, unified gene therapy approach, applicable to all patients with DBA regardless of which type of genetic mutation underlies their disease. The researchers have developed a gene therapy vector to achieve increased erythroid lineage-specific expression of GATA1. Based on preliminary data in DBA animal models, this approach enables sufficient GATA1 expression to overcome the underlying defects in DBA. This approach sets the stage for a first gene-therapy cure for DBA.

The projects were selected following an intensely competitive process focused on selecting the proposals with the greatest potential to address real, unmet medical needs and be ready for licensing to new companies or pharma/biotech within two years, said Ifat Rubin-Bejerano, senior director for translational research at HMS.

“Before they even applied, we helped many of the candidates shape their research plan, we helped them define ‘killer experiments’—critical experiments that help determine whether it’s worth investing more resources in a project,” said Rubin-Bejerano. “We helped candidates start thinking about the clinical and regulatory paths.”

“Now we are excited to nurture these promising projects within HMS and its affiliated hospitals, provide further scientific and translational guidance, and support and shepherd them to a point where they would be more likely to succeed in the real world.”